Assessment of Intranasal Glucagon in Children and Adolescents With Type 1 Diabetes: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Assessment of Intranasal Glucagon in Children and Adolescents With Type 1 Diabetes (NCT01997411), a randomized phase 2, phase 3 study. The primary outcome is Maximum Change From Baseline Concentration (Cmax) of Glucagon.

2. Clinical Question

3. Trial Design

The registry classifies this as a randomized, quadruple-masked, crossover study in Phase 2 and Phase 3. It enrolled 48 participants with type 1 diabetes. The listed interventions were nasal glucagon and intramuscular glucagon, and the trial status is completed. The registry lists a start in 2013-11 and primary completion in 2015-01.

The dosing groups were organized by age. Participants 4 to less than 8 years old and those 8 to less than 12 years old had nasal glucagon visits at both 2.0 mg and 3.0 mg, as well as an intramuscular glucagon visit. Participants 12 to less than 17 years old had a 3.0 mg nasal visit and an intramuscular visit. Intramuscular dosing depended on weight: 1 mg for participants weighing at least 25 kilograms and 0.5 mg for those weighing less than 25 kilograms.

A crossover design means that treatment conditions are assessed within participants across visits, rather than relying solely on a comparison between distinct treatment groups. That structure can support within-participant comparisons, but the registry record does not report the treatment sequence, visit spacing, washout arrangements, or the analysis used to account for repeated observations. The quadruple-masking label is reported, but the registry record does not identify which roles were masked.

The primary outcome population is described as enrolled participants who completed the required dosing visit or visits. The registry also notes one exclusion after nose-blowing following nasal administration and one withdrawal after completing a 3.0 mg nasal visit. Further details about the incomplete text describing the withdrawal are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Only the first 6 of 8 groups are shown.

Overall Study

Analysis population for the primary outcome, as defined in the registry: All enrolled participants that completed the required dosing visit(s). One participant in the 4 to \<8 year old 2.0 mg NG group was excluded due to blowing nose after NG administration. One participant in the 8 to \<12 group withdrew after completion of the 3.0 mg NG visit and did not complete the 2.0 mg NG visit.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Change From Baseline Concentration (Cmax) of Glucagon, measured over Pre-dose; 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration.

The primary endpoint was the maximum change from baseline concentration of glucagon, or Cmax, measured in picograms per millilitre. It summarizes the largest observed increase in glucagon concentration relative to the participant’s baseline during the scheduled measurement period. Concentrations were measured before dosing and at 5, 10, 15, 20, 30, 40, 60 and 90 minutes following glucagon administration.

This endpoint is used to describe the concentration response after dosing. Reporting the mean gives a group-level summary, while the standard deviation describes how spread out the individual observations are around that mean. Those summaries can characterize the observed concentration profiles, but they do not by themselves establish whether a difference between dosing visits is statistically distinguishable from chance or clinically important.

The registry reports age-specific visit groups and gives a mean and standard deviation for each. For participants 4 to less than 8 years old, the mean was 6290.0 pg/mL (standard deviation 2046.0) for the intramuscular visit, 3464.0 pg/mL (standard deviation 1760.0) for the 2.0 mg nasal visit, and 3959.0 pg/mL (standard deviation 2439.0) for the 3.0 mg nasal visit. These are descriptive summaries; the registry record does not report an inferential comparison for this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports descriptive means and standard deviations for a continuous endpoint. Those statistics summarize the observed concentration values in each listed visit group. They do not, on their own, answer whether treatments differ after accounting for the trial’s randomized crossover structure, nor do they convey the uncertainty around a treatment contrast.

What does the mean describe?

For a continuous measure, the mean is the arithmetic average of the observations in a group. Here, each reported mean summarizes maximum change from baseline glucagon concentration for an age-and-visit group. It is useful for describing the typical level in that group, but it can be affected by unusually high or low observations. It also does not describe how individual participants responded or whether a particular participant’s response was typical.

What does the standard deviation describe?

The standard deviation describes the spread of observations around the group mean. A larger standard deviation indicates greater dispersion in the observed values, while a smaller one indicates that values are more closely clustered around the mean. Standard deviation is not the same as a standard error, and it is not a confidence interval. The reported standard deviations therefore describe participant-level variability, not the precision of a treatment-effect estimate.

General statistical explanation: a confidence interval gives a range of values compatible with the data and the method used to calculate it, under its assumptions. It is commonly used to communicate uncertainty in an estimate. No confidence intervals for the primary outcome are reported in the registry record, so the precision of treatment contrasts cannot be assessed from the posted summaries alone.

Why does crossover structure matter?

In a crossover study, a participant can contribute observations under more than one treatment condition. A treatment comparison may therefore use the within-participant relationship between visits. General statistical explanation: when outcomes from the same person are correlated, an analysis that accounts for that correlation can differ in precision from an analysis that treats all observations as independent. The registry record identifies a crossover model but does not report the statistical model, the handling of visit or period effects, or whether the primary analysis used paired measurements.

The summaries list different participant counts across some visit groups. The registry describes the primary population as participants who completed the required dosing visit or visits and notes an exclusion and a withdrawal. The record does not report a complete participant flow by visit or explain the analysis population in enough detail to determine how missing visit measurements were handled.

Why are treatment contrasts needed?

A comparison of treatments is usually expressed as a contrast, such as a difference in means, together with an estimate of uncertainty. In a crossover study, that contrast would ideally reflect the design and account for repeated measurements. The registry record reports group means and standard deviations, but does not report such a contrast, its confidence interval, or a test statistic for the primary outcome. No new contrast should be inferred from the separate summaries.

General statistical explanation: over-dispersion means that observations vary more than a statistical model assumes. If a model underestimates variability, its standard errors can be too small and its uncertainty intervals too narrow. The posted primary outcome is continuous and summarized with means and standard deviations; the registry record does not report a model diagnosing over-dispersion or an analysis that requires such an adjustment. This concept should not be mistaken for a finding from this trial.

What do the planning assumptions mean?

Any sample-size illustrations associated with the results are planning exercises rather than observed trial outcomes. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Such illustrations ask how many participants per arm might be needed under those assumptions. They are not the trial’s original design justification, and they are not observed power. The registry record does not report the original sample-size justification, the effect size used in its planning, or a statistical analysis plan.

The record indicates that values were missing or not estimable for a two-arm comparison of this continuous endpoint. That limitation is consistent with caution about treating the visit-group summaries as if they were a conventional two-arm parallel-group comparison. The posted data provide descriptive information, but they do not include the inferential quantities needed to quantify uncertainty for a treatment contrast.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("4 to<8 Years Old IM Glucagon Visit", "4 to<8 Years Old NG Visit 2.0 mg", "4 to<8 Years Old NG Visit 3.0 mg", "8 to <12 Years Old IM Glucagon Visit", "8 to<12 Years Old NG Visit 2.0 mg", "8 to<12 Years Old NG Visit 3.0 mg")
n   <- c(6, 11, 12, 6, 11, 12)
m   <- c(6290.33, 3463.55, 3958.58, 4743, 2776.27, 5664.33)
sp  <- c(2045.96, 1760.28, 2438.6, 3094.61, 979.28, 2114.69)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  4 to<8 Years Old IM Glucagon Visit  6  6290.330  2045.960  4143.227  8437.433
CARM  4 to<8 Years Old NG Visit 2.0 mg  11  3463.550  1760.280  2280.978  4646.122
CARM  4 to<8 Years Old NG Visit 3.0 mg  12  3958.580  2438.600  2409.167  5507.993
CARM  8 to <12 Years Old IM Glucagon Visit  6  4743.000  3094.610  1495.406  7990.594
CARM  8 to<12 Years Old NG Visit 2.0 mg  11  2776.270  979.280  2118.381  3434.159
CARM  8 to<12 Years Old NG Visit 3.0 mg  12  5664.330  2114.690  4320.720  7007.940

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 10 outcome measures and reports three secondary outcomes: nasal and non-nasal effects or symptoms, the number of participants with at least a 25 mg/dL rise in blood glucose above nadir within 30 minutes, and time to that rise in plasma glucose within 30 minutes. Numerical results for these secondary outcomes are not reported in the registry record. The record also lists zero analyses. A plan for controlling multiplicity across outcomes or comparisons is not reported in the registry record.

Multiplicity matters when several outcomes, doses, age groups, or treatment contrasts are examined. General statistical explanation: the more comparisons that are made, the greater the chance that at least one result may appear unusual by chance alone. Prespecified methods can address that issue, but no such method is described in the registry record. It is therefore not possible to determine whether the posted outcome summaries were part of a prespecified hierarchy or how multiple testing was handled.

The primary outcome population is described as all enrolled participants who completed the required dosing visit or visits. The record notes that one participant in the 4 to less than 8 years 2.0 mg nasal group was excluded after blowing their nose following nasal administration. It also notes that one participant in the 8 to less than 12 years group withdrew after completing the 3.0 mg nasal visit. The remaining details in that withdrawal description and the full missing-data handling are not reported in the registry record.

The record does not report whether missing observations were imputed, whether analyses were restricted to complete visits, or whether sensitivity analyses were conducted. Nor does it describe an intention-to-treat analysis population. Because the design is crossover, missing a visit may affect the availability of within-participant comparisons; the registry does not explain how that issue was addressed. The reported group counts should therefore be interpreted as the counts attached to the posted summaries, not as a complete account of every participant’s contribution across visits.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hypoglycemia (16.7%).

The registry reports serious adverse events and other adverse events by age and visit group. One participant in the 4 to less than 8 years intramuscular glucagon group was affected by a serious adverse event, with 6 participants at risk in that group. The listed serious term is hypoglycemia, reported at 16.7%. No serious adverse events are listed as affecting participants in the other reported age-and-visit groups.

The “other” adverse-event counts are separate summaries: 5 of 6 participants in the 4 to less than 8 years intramuscular group were affected; the corresponding counts were 6 of 12 for 2.0 mg nasal glucagon and 5 of 12 for 3.0 mg nasal glucagon. In the 8 to less than 12 years group, the counts were 6 of 6 for intramuscular glucagon, 5 of 11 for 2.0 mg nasal glucagon and 6 of 12 for 3.0 mg nasal glucagon. In the 12 to less than 17 years group, the counts were 7 of 12 for intramuscular glucagon and 9 of 12 for 3.0 mg nasal glucagon.

These are participant counts within visit groups, not evidence that an event was caused by a treatment. The registry record does not report a comparative safety analysis or enough detail to assess event severity beyond the serious-event classification. Death counts are not reported in the registry record.

13. What the Result Does, and Does Not, Mean

The posted results show group-level summaries of maximum change from baseline glucagon concentration following nasal and intramuscular dosing visits. They also report the number of participants contributing to each summary and the standard deviation within each group. This makes it possible to describe the observed concentrations and their variability by age group and visit.

The summaries do not establish whether the treatments differ statistically. No confidence intervals, p-values, or formal treatment contrasts for the primary endpoint are reported in the registry record. Since the study is crossover, a direct interpretation would ideally account for each participant’s measurements across visits. The group summaries do not show the paired differences or their uncertainty, and the correlation between visits cannot be recovered from the means and standard deviations alone.

These results also do not establish the size or importance of any effect for a clinical decision. The registry record does not report a threshold for a clinically meaningful concentration change. The listed secondary outcomes concern symptoms and blood-glucose response, but their numerical results are not reported in the registry record. The primary concentration endpoint should not be treated as a substitute for those outcomes.

The safety listings describe affected-participant counts by visit group, including one serious event in the youngest intramuscular group and no serious events listed in the other reported groups. These counts are descriptive and do not establish a causal relationship or a comparative safety difference. The registry record does not report a formal comparison of adverse-event rates.

Accordingly, the data support a descriptive account of the measured concentrations and reported adverse events in this completed trial. They do not, by themselves, establish comparative efficacy, clinical importance, or a treatment recommendation. Interpretation is also limited by the absence of the full analysis plan, treatment-contrast estimates, uncertainty intervals and detailed missing-data handling in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates why design information and result summaries need to be read together. Its randomized crossover structure differs from a conventional parallel-group design: participants can be measured under multiple dosing conditions, so the relevant comparison may depend on within-participant information. The registry reports age-specific visit-group means and standard deviations, but not the paired treatment contrasts or the analysis used to account for repeated measurements.

The posted summaries also make variability visible. Standard deviations differ across the listed groups, and some group sizes are small. That matters because group means alone can make differences appear more definitive than the data justify. Without confidence intervals or a reported treatment comparison, readers cannot assess the precision of the contrast from the registry results.

The record also illustrates the distinction between an outcome’s measurement and its clinical interpretation. The primary endpoint measures a change in glucagon concentration over scheduled post-dose times. Other listed outcomes address symptoms and blood-glucose response, but their numerical results are not reported in the registry record. A concentration summary does not answer every question about a treatment’s effects.

Finally, reporting of analysis populations, missing visits, multiplicity, and safety comparisons is important for understanding how results were produced and how broadly they can be interpreted. The registry identifies an exclusion and a withdrawal, but the full missing-data approach and statistical plan are not reported. Those gaps do not erase the descriptive results; they limit the strength of conclusions that can be drawn from them.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record does not report inferential results for the primary endpoint: there are no treatment contrasts, confidence intervals, p-values, or test statistics. The descriptive means and standard deviations cannot establish the statistical precision of comparisons. This is especially relevant for a crossover study, where paired information and within-participant correlation may matter, but the record does not describe how those features were analyzed.

The primary outcome population is described as participants completing the required dosing visit or visits. The record notes an exclusion after nose-blowing following nasal administration and a withdrawal after a 3.0 mg nasal visit, but it does not provide a complete account of missing observations or their handling. Details of visit order, visit spacing, washout, and possible period effects are also not reported in the registry record.

Group sizes vary across the posted primary endpoint summaries, and several groups have relatively few participants. The record does not report a sample-size justification or the original statistical analysis plan. It also does not report how multiplicity across outcomes, age groups, doses, or comparisons was addressed. Numerical results for the listed secondary outcomes are not reported in the registry record, limiting interpretation beyond the concentration endpoint.

The safety information is presented as affected-participant counts by visit group, without a reported comparative analysis. The registry record does not report deaths, and it does not provide enough information to infer causality from event counts. These limitations restrict interpretation to the descriptive outcomes and safety counts that are posted.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Assessment of Intranasal Glucagon in Children and Adolescents With Type 1 Diabetes — NCT01997411.
• Registry record last updated 2018-08-29; status last verified 2018-08.
• Results first posted 2017-03-06.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

This completed randomized, quadruple-masked crossover study enrolled 48 children and adolescents with type 1 diabetes and is listed in Phase 2 and Phase 3. It assessed nasal glucagon and intramuscular glucagon across age-specific dosing visits. The primary endpoint was maximum change from baseline glucagon concentration, measured before dosing and at scheduled times through 90 minutes, and summarized by mean and standard deviation.

The registry reports eight age-and-visit group summaries and adverse-event counts. It lists three secondary outcomes, but their numerical results are not reported in the registry record. Formal treatment contrasts, confidence intervals, p-values, the statistical analysis plan, and detailed missing-data methods are also not reported. The results therefore describe observed group summaries without establishing the precision or clinical importance of treatment differences.